This application extends a previously funded investigation among low-income, urban African American children through longitudinal follow-up into adolescence. The Experimental Group (High or Low Exposure) was prenatally exposed to cocaine, documented by toxicology tests at delivery. A comparison group was comprised of an unexposed matched sample of children from the same community. This translational application has two phases. The first phase examines how prenatal substance exposure is related to proximal brain functioning during adolescence, assessed through neuropsychological measures of attention, memory, and executive functioning; the neural correlates of working memory and response to risk and reward evaluation measured by fMRI; and diurnal rhythms of salivary cortisol. Because prenatal substance exposure often occurs in the context of environmental challenges (poverty, ongoing drug use, and disruptions in care), the application will examine whether the effects of prenatal substance exposure are moderated by environmental factors. In the second phase, the application will examine how prenatal substance exposure is related to adolescents' distal functioning via academic performance, socio-emotional development, and early drug use (marijuana). Response to acute challenges, measured by salivary cortisol, will be used to understand the adolescents' ability to adapt to environmental pressures and ultimately their resilience or vulnerability to early drug use. The application will examine whether the relationship from prenatal substance exposure to distal behavior is direct or mediated through proximal brain functioning. With developmental-ecological theory as a guide, a multi-method, multi-informant strategy is used, incorporating reports from adolescents, caregivers, and teachers; standardized measures of neuropsychological, academic, and socioemotional performance; brain imaging; and biomarkers of the stress response (salivary cortisol) and drug use (hair and urine). This application examines adacemic performance, socio-emotional functioning, and drug use among adolescents exposed to cocaine and/or heroin prenatally